2-phenyl benzimidazole derivatives as MCP-1 antagonists

ABSTRACT

The present invention relates to novel compounds and medical methods of treatment of inflammation, atherosclerosis, restenosis, and immune disorders especially those associated with lymphocyte or monocyte accumulation such as arthritis and transplant rejection. More particularly, the present invention concerns the use of 2-phenyl benzimidazole derivatives.

This Application is a 371 of PTC/497/13870 filed Aug. 6, 1997 and claimsthe benefit of Provisional application Ser. No. 60,023,942 filed Aug.14, 1996.

FIELD OF THE INVENTION

The present invention relates to novel compounds and medical methods oftreatment of inflammation, atherosclerosis, restenosis, and immunedisorders especially those associated with lymphocyte or monocyteaccumulation such as arthritis and transplant rejection. Moreparticularly, the present invention concerns the use of 2-phenylbenzimidazole derivatives.

BACKGROUND OF THE INVENTION

Migration of leukocytes from blood vessels into diseased tissues isimportant to the initiation of normal disease-fighting inflammatoryresponses. But this process, known as leukocyte recruitment, is alsoinvolved in the onset and progression of debilitating andlife-threatening inflammatory and autoimmune diseases. The pathology ofthese diseases results from the attack of the body's immune systemdefenses on normal tissues. Thus, blocking leukocyte recruitment totarget tissues in inflammatory and autoimmune disease would be a highlyeffective therapeutic intervention. The leukocyte cell classes thatparticipate in cellular immune responses include lymphocytes, monocytes,neutrophils, eosinophils and basophils. In many cases, lymphocytes arethe leukocyte class that initiates, coordinates, and maintains chronicinflammatory responses, and thus are generally the most important classof cells to block from entering inflammatory sites. Lymphocytes attractmonocytes to the site, which, collectively with lymphocytes, areresponsible for much of the actual tissue damage that occurs ininflammatory disease. Infiltration of lymphocytes and/or monocytes isresponsible for a wide range of chronic, autoimmune diseases, and alsoorgan transplant rejection. These diseases include, but are not limitedto, rheumatoid arthritis, atherosclerosis, psoriasis, chronic contactdermatitis, inflammatory bowel disease, multiple sclerosis, sarcoidosis,idiopathic pulmonary fibrosis, dermatomyositis, skin pemphigoid andrelated diseases, (e.g., pemphigus vulgaris, p. foliacious, p.erythematosis), glomerulonephritides, vasculitides, hepatitis, diabetes,allograft rejection, and graft-versus-host disease.

This process, by which leukocytes leave the bloodstream and accumulateat inflammatory sites, and initiate disease, takes place in at leastthree distinct steps which have been described as (1) rolling, (2)activation/firm adhesion and (3) transendothelial migration [Springer,T. A., Nature 346:425-433 (1990); Lawrence and Springer, Cell 65:859-873(1991); Butcher, E. C., Cell 67:1033-1036 (1991)]. The second step ismediated at a molecular level by chemoattractant receptors.Chemoattractant receptors on the surface of leukocytes bindchemoattractant cytokines secreted by cells at the site of damage orinfection. Receptor binding activates leukocytes, increases theadhesiveness of the adhesion molecules that mediate transendothelialmigration, and promotes directed migration of the cells toward thesource of the chemoattractant cytokine.

A recent discovery is the existence of a large family (>20 members) ofstructurally homologous chemoattractant cytokines, approximately 8 to 10kD in size. These molecules share the ability to stimulate directed cellmigration (chemotaxis) and have been collectively called “chemokines”, acontraction of chemotactic cytokines. Each chemokine contains fourcysteine residues (C) and two internal disulfide bonds. Chemokines canbe grouped into two subfamilies, based on whether the two amino terminalcysteine residues are immediately adjacent (C-C family) or separated byone amino acid (C-X-C family). These differences correlate with theorganization of the two subfamilies into separate gene clusters. Withineach gene cluster, the chemokines typically show sequence similaritiesbetween 25 to 60%.

The chemokines of the C-X-C subfamily, such as interleukin-8, areproduced by a wide range of cell types and act predominantly onneutrophils as mediators of acute inflammation. Chemokines of the C-Csubfamily are also produced by a wide variety of cell types. Thesemolecules act predominantly on subsets of mononuclear inflammatorycells. Currently there are at least six C-C chemokines with knownchemotactic activity for human monocytes and/or T cells, includingMCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, and RANTES. This suggests there maybe a high degree of redundancy in chemoattractant pathways. In addition,most C-C chemokines are chemotactic for more than one cell type. Forexamples, RANTES (regulated on activation, normal T cell expressed andsecreted) acts on memory CD4⁺ T cells, eosinophils, and monocytes.Monocyte chemoattractant protein-1 (MCP-1), another C-C chemokine, actson monocytes, activated “memory” T cells and on basophils. MCP-1 is alsoa potent secretogogue of inflammatory mediators for monocytes andbasophils.

Five C-C chemokine receptors have recently been characterized (CKR1-5 orCCR1-CCR5), and all of these belong to the seven transmembrane spanningG protein-coupled receptor family. Each of these receptors mediates thebinding and signaling of more than one chemokine. For example, the CCR1receptor binds both MIP-1α and RANTES. There are 2 receptors which bindMCP-1, CCR2 (with alternately spliced forms, 2A and 2B) and CCR4. CCR2is also known to mediate binding and signaling of MCP-3. The CCR4receptor binds and signals, in addition to MCP-1, with RANTES andMIP-1α. Which of these is responsible for the MCP-1 mediated recruitmentof monocytes and T cells is not known.

In agreement with the observation that lymphocyte emigration intoinflammatory sites is usually accompanied by emigration of monocytes,MCP-1 is expressed at sites of antigen challenge and autoimmune disease.However, analyses of human inflammatory lesions with antibodies to otherchemokines show RANTES, MIP-1α, MIP1β and MCP-3 to be present as well.Injection of MCP-1 into skin sites in mice provokes only a mildmonocytic infiltrate or no infiltrate at all (Ernst, C. A. et al., J.Immunol. 152:3541-3544, 1994). Whether these results reflect redundantand complex recruitment pathways has not been resolved. MCP-1 and MCP-3may play a role in allergic hypersensitivity disease. This is suggestedby the observation that MCP-1 lacking the amino terminal glutamic acidloses the ability to stimulate basophil mediator release and acquiresactivity as an eosinophil chemoattractant.

Chemokines of both subfamilies may bind to heparan sulfate proteoglycanson the endothelial cell surface, and may function principally tostimulate haptotaxis of leukocytes that attach to cytokine-activatedendothelium through induced adhesion molecules. Additionally, MCP-1 hasbeen reported to selectively activate the β1 integrin family ofleukocyte adhesion molecule, suggesting a role in leukocyte interactionswith the extracellular matrix. Hence, MCP-1 may not only trigger theinitial arrest and adhesion of monocytes and T cells, but may also actto guide their migration in extravascular space.

Chemoattractants appear to be required for transendothelial migration invitro and in vivo and can induce all steps required for transmigrationin vivo. Injection of neutrophil chemoattractants into skin or muscleleads to robust emigration of neutrophils from the vasculature andaccumulation at the injection site (Colditz, 1991). Pretreatment ofneutrophils with pertussis toxin inhibits emigration into inflammatorysites (Spangrude, et al., 1985; Nourshargh and Williams, 1990).Moreover, MAb to IL-8 markedly inhibits neutrophil emigration ininflammation (Sekido et al., 1993).

Neutrophil chemoattractants injected into the same skin site hours apartwill stimulate neutrophil accumulation the first time but not the secondtime, whereas a second injection into a distant site will stimulateaccumulation at that site. This desensitization occurs for homologouschemoattractants only (Colditz, 1991) or those that interact with thesame receptor. Thus, chemoattractants can act on and homologouslydesensitize a cell type that is localized in tissue.

Chemoattractants impart directionality to leukocyte migration. Bycontrast with intradermal injection, intravascular injection of IL-8does not lead to emigration (Hechtman et al., 1991). Cytokine-stimulatedendothelial monolayers grown on filters secrete IL-8 into the underlyingcollagen layer. Neutrophils added to the apical compartment emigrateinto the basilar compartment, but not when the IL-8 gradient isdisrupted by addition of IL-8 to the apical compartment (Huber et al.,1991).

The endothelium may present chemoattractants to leukocytes in afunctionally relevant way, as well as providing a permeability barrierthat stabilizes the chemoattractant gradient. Since leukocytes,responding to specific antigen or inflammatory signals in tissue, maysignal emigration of further leukocytes into the site, a chemoattractantwas sought in material secreted by mitogen-stimulated mononuclear cells(Carr et al., 1994). Purification to homogeneity guided by atransendothelial lymphocyte chemotaxis assay revealed that monocytechemoattractant protein 1 (MCP-1), previously thought to be solely amonocyte chemoattractant, is a major lymphocyte chemoattractant. Anactivated subset of memory lymphocytes respond to MCP-1. In the sameassay, lymphocytes respond to RANTES and MIP-1α but less so than toMCP-1 (C-C chemokines) and not at all to IL-8 or IP-10 (C-X-Cchemokines). This physiologically relevant assay suggests that C-Cchemokines tend to attract both monocytes and lymphocytes. In agreementwith the observation that lymphocyte emigration into inflammatory sitesis accompanied by emigration of monocytes, MCP-1 is abundantly expressedat sites of antigen challenge and autoimmune disease (Miller andKrangel, 1992) and, together with other chemokines, is an excellentcandidate to provide the step 2 signal required to activate integrinadhesiveness and emigration of lymphocytes in vivo. (Traffic Signals forLymphocyte Recirculation and Leukocyte Emigration: The MultistepParadigm; Springer, 1994, Cell 76: 301-314).

We have surprisingly found that 2-phenyl benzimidazole derivates areMCP-1 receptor antagonists and are capable of inhibiting the binding ofMCP-1 to its receptor. Surprisingly, the compounds block T cellmigration in vitro, and more surprisingly still, have dramatic effectson the recruitment of inflammatory cells in multiple models ofinflammatory diseases. Thus, these compounds are useful as agents forthe treatment of inflammatory disease, especially those associated withlymphocyte and/or monocyte accumulation, such as arthritis,atherosclerosis and transplant rejection. In addition, these compoundscan be used in the treatment of allergic hypersensitivity disorders suchas asthma and allergic rhinitis characterized by basophil activation andeosinophil recruitment, as well as for the treatment of restenosis andchronic or acute immune disorders.

SUMMARY OF THE INVENTION

Accordingly, a first embodiment of the present invention provides amethod of treatment of chronic or acute inflammatory disease,atherosclerosis, restenosis, chronic or acute immune disorders, andtransplant rejection in mammals in need thereof comprising administeringto such mammal an effective amount of a 2-phenyl benzimidazole ofFormula I or a pharmaceutically acceptable salt thereof:

wherein A is N or CH;

W, X, Y, and Z can be independently C—R₂, C—R₃, C—R₄, C—R₅, or N,

no more than two of W, X, Y, and Z can be N in any one structure,

R₂, R₃, R₄, and R₅ can be independently

H,

C₁₋₂₀ alkyl,

halogen,

nitro,

—SO₂NR₈R₉,

alkoxy of from 1-4 carbon atoms,

—S(O)_(p)R where p is an integer of from 0 to 2,

—(CH₂)_(m)OR,

—(CH₂)_(m)COOR,

—(CH₂)_(m)NR₈R₉,

—(CH₂)_(m)CONR₈R₉,

—(CH₂)_(m)COR,

—CF₃,

-benzyl, or

phenyl wherein benzyl or phenyl is optionally substituted with one ortwo substituents each independently selected from alkyl, halogen,hydrogen, hydroxy, or alkoxy;

m is an integer of from 0 to 4,

R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10carbon atoms or benzyl;

when X and Y are substituted by alkyl, they can be joined to form a ringfused at X and Y;

R₁ is H, lower alkyl of from 1-4 carbon atoms, or —(CH₂)_(m)-Ph;

R′₂ is:

H,

C₁₋₂₀ alkyl,

halogen,

nitro,

—SO₂NR₈R₉,

alkoxy of from 1-4 carbon atoms,

—S(O)_(p)R wherein p is an integer of from 0 to 2,

—(CH₂)_(m)OR₁—CH₂COOR,

—(CH₂)_(m)NR₈R₉,

—(CH₂)_(m)CONR₈R₉,

—(CH₂)_(m)COR, or

—CF₃;

R₆ is hydrogen, alkyl of from 1 to 6 carbon atoms or R₇;

R₇ is (CH₂)_(n)NR₁₀R₁₁;

n is an integer from 2 to 6;

R₈ and R₉ can be independently hydrogen, lower alkyl of from 1-4 carbonatoms or can be taken together to form a ring of from 3-8 atoms havingup to one additional heteroatom as O, S, SO₂, or N—R₁₂;

R₁₀ and R₁₁ can independently be lower alkyl,

—(CH₂)_(m)Ph, unsubstituted or substituted with up to three R₂substituents, or

R₁₀ and R₁₁ can be taken together to form a ring of from 3 to 8 atomswhich may contain oxygen or NR₁₂;

R₁₂ is

hydrogen,

lower alkyl,

—(CH₂)_(t)Ph, where Ph is phenyl unsubstituted or substituted with up tothree R₂ substituents;

t is an integer of from 0 to 2;

or a pharmaceutically acceptable salt thereof.

A still further and second embodiment of the present invention is amethod of treatment of atherosclerosis in mammals in need thereofcomprising administering to such mammal an effective amount of acompound selected from the group consisting of: a compound of Formula Iin combination with one or more agents selected from the groupconsisting of:

(a) ACAT inhibitor;

(b) HMG-CoA reductase inhibitor;

(c) Lipid regulator; and

(d) Bile acid sequestrant;

or a pharmaceutically acceptable salt thereof.

Also, the invention is directed to inhibiting the binding of MCP-1 byutilizing an effective inhibiting amount of a compound of Formula I.

Also, the invention is directed to the novel compositions of Formula I.

Finally, the present invention is directed to a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the dose response of Example 1 in a rat glucan vasculitisassay.

FIG. 2 is a graphic illustration of the degree of inhibition of T cellrecruitment in rat DHR over a 24 hour period at various doses ofCompound 1. There was a statistically significant inhibitory effect ofthe compound when administered at 30 and 23 mg/kg per os at the time ofantigen challenge.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term “lower alkyl” means a straightor branched hydrocarbon radical having from 1 to 4 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, or tert-butyl.

The term “lower alkoxy” is O-alkyl as defined above for lower alkyl.

“Halogen” is fluorine, chlorine, bromine, or iodine.

Preferably, heterocycle is five or six-membered mono or bicyclic ringstructures which may contain one or more heteroatom such as N or O;examples of heterocycle are pyridine, pyrimidine, pyridazine, pyrazole,oxazole, indole, N-alkylindole, quinoline, quinazoline, quinazolinoneand the like. Substituents can be hydrogen, alkyl of from 1-4 carbonatoms; cycloalkyl of from 5-7 carbon atoms, OR₁, SR₁, —NR₈R₉,(CH₂)_(n)—NR₈R₉, —COOR₁, —CH₂OR₁, —CONR₈R₉, —COR₁, —CH₂CONR₈R₉,SO₂NR₈R₉, NHCOR₁, NR₁CONR₈ where R₁, R₈ and R₉ are as defined above;—CN, or halogen.

The term “mammal” includes animals and humans.

Some of the compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, 2-phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,“Pharmaceutical Salts,” J. Pharma. Sci., 1977;66:1).

The acid addition salts of said basic compounds can be prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms can differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents.

Pharmaceutically acceptable base addition salts can be formed withmetals or amines, such as alkali and alkaline earth metals or organicamines. Examples of such metals used as cations are sodium, potassium,magnesium, calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (seeBerge, Supra, 1977).

The base addition salts of said acidic compounds can be prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner. The free acid formscan differ from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms andare intended to be encompassed within the scope of the presentinvention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

A preferred compound of the first embodiment used in the method of thepresent invention is a compound Formula I of:

wherein A is N or CH;

W, X, Y, and Z can be independently C—R₂, C—R₃, C-R₄, C—R₅, or N;

no more than two of W, X, Y, and Z can be N in any one structure,

R₂, R₃, R₄, and R₅ can be independently

H,

C₁₋₂₀ alkyl,

halogen,

nitro,

—SO₂NR₈R₉,

alkoxy of from 1-4 carbon atoms;

—S(O)_(p)R where p=0-2;

—(CH₂)_(m)OR,

—(CH₂)_(m)COOR,

—(CH₂)_(m)NR₈R₉,

—(CH₂)_(m)CONR₈R₉,

—(CH₂)_(m)COR, or

—CF₃,

-benzyl, or

phenyl wherein benzyl or phenyl is optionally substituted with one ortwo substituents each independently selected from alkyl, halogen,hydrogen, hydroxy, or alkoxy;

when X and Y are substituted by alkyl, they can be joined to form a ringfused at X and Y;

m is an integer of from 0-4,

R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10carbon atoms (such as phenyl or naphthyl) or benzyl;

R₁ can be H, lower alkyl of from 1-4 carbon atoms, or —(CH₂)_(m)-Ph;

R₆ is hydrogen or alkyl of from 1-6 carbon atoms or R₇;

R₇ is (CH₂)_(n)NR₁₀R₁₁;

n is an integer from 2 to 6;

R₈ and R₉ can be independently hydrogen, lower alkyl of from 1-4 carbonatoms or can be taken together to form a ring of from 3-8 atomscontaining up to one additional heteroatom as oxygen, S, SO₂, or N—R₁₂;

R₁₀ and R₁₁ can independently be lower alkyl,

—(CH₂)_(t)Ph, unsubstituted or substituted with up to three R₂substituents, or

R₁₀ and R₁₁ can be taken together to form a ring of from 3-8 atoms whichmay contain oxygen or NR₁₂;

R₁₂ is

hydrogen,

lower alkyl,

—(CH₂)_(t)Ph, where Ph is phenyl, unsubstituted or substituted with upto three R₂ substituents;

t is an integer of from 0 to 2;

or a pharmaceutically acceptable salt thereof.

Examples of preferred benzimidazoles are as follows:

and they are as described above for Formula I.

A benzimidazole compound can be administered to a mammal (e.g., a human)alone or in conjunction with (before, along with or subsequent to) oneor more other benzimidazole compounds or another agent to beadministered.

Preferred compounds used in the second embodiment of the presentinvention include one or more agents selected from the group consistingof an acyl CoA:cholesterol acyltransferase (ACAT) inhibitor;3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMG-CoA reductase)inhibitor; lipid regulator; and bile acid sequestrant.

Examples of ACAT inhibitors include DL-melinamide disclosed in BritishPatent 1,123,004 and Japan. J. Pharmacol., 1986;42:517-523;2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide disclosed in U.S.Pat. No. 4,716,175;N-[2,6-bis(1-methylethyl)phenyl]-N′-[[1-(4-dimethylaminophenyl)cyclopentyl]-methyl]ureadisclosed in U.S. Pat. No. 5,015,644;2,6-bis(1-methylethyl)-phenyl[[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamatedisclosed in copending U.S. patent application Ser. No. 08/233,932 filedApr. 13, 1994; and the like. U.S. Pat. Nos. 4,716,175 and 5,015,644 andU.S. patent application Ser. No. 08/233,932 and British Patent 1,123,004and Japan. J. Pharmacol., 1986;42:517-523 are hereby incorporated byreference.

Examples of HMG-CoA reductase inhibitors include lovastatin disclosed inU.S. Pat. No. 4,231,938; pravastatin disclosed in U.S. Pat. No.4,346,227; simvastatin disclosed in U.S. Pat. No. 4,444,784; fluvastatindisclosed in U.S. Pat. No. 4,739,073; atorvastatin disclosed in U.S.Pat. Nos. 4,681,893 and 5,273,995; and the like. U.S. Pat. Nos.4,231,938; 4,346,227; 4,444,784; 4,681,893; 4,739,073 and 5,273,995 arehereby incorporated by reference.

Examples of bile acid sequestrants include colestipol disclosed in U.S.Pat. Nos. 3,692,895 and 3,803,237; cholestyramine disclosed in U.S. Pat.No. 3,383,281 and Casdorph R. in Lipid Pharmacology., 1976;2:222-256,Paoletti C., Glueck J., eds. Academic Press, N.Y.; and the like. U.S.Pat. Nos. 3,692,895; 3,803,237 and 3,383,281 and R. Casdorph, supra,1976, are hereby incorporated by reference.

Examples of lipid regulators include gemfibrozil described in U.S. Pat.No. 3,674,836; bezafibrate disclosed in U.S. Pat. No. 3,781,328;clofibrate disclosed in U.S. Pat. No. 3,262,850; fenofibrate disclosedin U.S. Pat. No. 4,058,552; niacin disclosed in McElvain, et al., Org.Syn., 1925;4:49; and the like. U.S. Pat. Nos. 3,674,836; 3,781,328;3,262,850 and 4,058,552 and McElvain, et al., Org. Syn., 1925;4:49 arehereby incorporated by reference.

Methods of preparing ACAT inhibitors, HMG-CoA reductase inhibitors,lipid regulators, and bile acid sequestrants used in the secondembodiment of the present invention are disclosed in the aforementionedreferences.

The invention is also concerned with novel compounds as benzimidazolederivatives:

A compound of Formula I

wherein A is Nor CH;

W, X, Y, and Z can be independently C—R₂, C—R₃, C—R₄, C—R₅, or N,

no more than two of W, X, Y, and Z can be N in any one structure,

R₂, R₃, R₄, and R₅ can be independently

H,

C₁₋₂₀ alkyl,

halogen,

nitro,

—SO₂NR₈R₉,

alkoxy of from 1-4 carbon atoms;

—S(O)_(p)R where p is an integer of from 0 to 2;

—(CH₂)_(m)OR,

—(CH₂)_(m)COOR,

—(CH₂)_(m)NR₈R₉,

—(CH₂)_(m)CONR₈R₉,

—(CH₂)_(m)COR, or

—CF₃;

m is an integer of from 0 to 4,

R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10carbon atoms, or benzyl;

R₁ can be H, lower alkyl of from 1-4 carbon atoms, or —(CH₂)_(m)-Ph;

R₆ is hydrogen or alkyl of from 1-6 carbon atoms or R₇;

R₇ is (CH₂)_(n)NR₁₀R₁₁;

n is an integer from 2 to 6;

R₈ and R₉ can be independently hydrogen, lower alkyl of from 1-4 carbonatoms or can be taken together to form a ring of from 3-8 atoms havingup to one additional heteroatom as O, S, SO₂, or N—R₁₂;

R₁₀ and R₁₁ can independently be lower alkyl,

—(CH₂)_(m)Ph, unsubstituted or substituted with up to three R₂substituents, or

R₁₀ and R₁₁ can be taken together to form a ring of from 3-8 atoms whichmay contain oxygen or NR₁₂;

R₁₂ is

hydrogen,

lower alkyl,

—(CH₂)_(t)Ph, where Ph is phenyl unsubstituted or substituted with up tothree R₂ substituents;

t is an integer of from 0 to 2;

or a pharmaceutically acceptable salt thereof.

General Synthesis

Compounds of Formula I can be synthesized as follows:

Scheme A

Where A is N

DDQ means 2,3-dichloro-5,6-dicyanobenzoquinone.

Where A is CH

The benzimidazoles are valuable agents for the treatment of inflammatorydiseases or conditions, atherosclerosis, restenosis, and autoimmunedisorders such as arthritis and transplant rejection.

In a preferred embodiment, the disease or condition is one which isassociated with lymphocyte and/or monocyte infiltration of tissues(including recruitment and/or accumulation in tissues), such asarthritis (e.g., rheumatoid arthritis), inflammatory bowel diseases(e.g., Crohn's disease, ulcerative colitis), multiple sclerosis,idiopathic pulmonary fibrosis, and graft rejection (e.g., intransplantation), including allograft rejection or graft-versus-hostdisease. In addition, diseases characterized by basophil activationand/or eosinophil recruitment, including allergic hypersensitivitydisorders such as asthma and allergic rhinitis can be treated accordingto the present invention.

Other diseases that may be treated with the benzimidazole of Formula Iare: psoriasis, chronic contact dermatitis, sarcoidosis,dermatomyositis, skin phemphigoid and related diseases (e.g., pemphigusvulgaris, p. foliacious, p. erythematosus), glomerulonephritides,vasculitides (e.g., necrotizing, cutaneous, and hypersensitivityvasculitis), hepatitis, diabetes, systemic lupus erythematosus andmyasthenia gravis.

In addition to psoriasis, other inflammatory dermatoses such asdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria and reperfusion injury can also be treated.

MCP-1 Binding Assay

Membranes used in the MCP-1 binding assay were prepared from THP-1 cells(human monocytic cell line source—American Type Culture Collection,Tumor Immunology Bank #202, Rockville, Md., accession no. ATCC TIB 202).Cells were harvested by centrifugation and washed twice in ice-cold PBS(phosphate-buffered saline) and the cell pellet was frozen at −80° C. insome cases. Cells were resuspended in ice-cold lysis buffer 5 mM HEPES(2-(4N-[2-hydroxyethyl]piperazin-1-yl)-N′-(2-ethanesulfonic acid), pH7.5, 2 mM EDTA (ethylenediaminetetraacetic acid), 5 μg/mL eachleupeptin, aprotinin, chymostatin (protease inhibitors), and 100 μg/mLPMSF (phenylmethane sulfonyl fluoride—also a protease inhibitor)) at aconcentration of 5×10⁷ cells/mL. The cell suspension was dounced 10-15times using the B pestle (small pestle of tissue grinder—clearance is0.07 mm; source—Fisher Scientific) on ice. Nuclei and debris wereremoved by centrifugation at 500-1000×g for 10 minutes at 4° C. Thesupernatant was transferred to a fresh tube and centrifuged at 25,000×gfor 30 minutes at 4° C. The supernatant was aspirated and the pellet wasresuspended in freezing buffer (10 mM HEPES, pH 7.5, 300 mM sucrose, 1μg/mL each leupeptin, aprotinin, chymostatin, and 10 μg/mL PMSF) using aminihomogenizer until all clumps were resolved. Membranes were aliquotedand frozen at minus 70-85° C. until needed. Typical binding assays used10-20 μg/well of total membrane protein as determined with a standardprotein assay (e.g. Bradford protein assay, BioRad, Richmond, Calif.).

For binding, 10-20 μg of total membrane protein were included in thebinding reaction along with 0.2 nM I¹²⁵-labeled MCP-1 (Amersham,Arlington Heights, Ill.) with or without unlabeled competitor MCP-1(Peprotech, Rocky Hill, N.J.) (at 500 nM). Binding reactions wereperformed in a final volume of 100 ul in a binding buffer containing 10mM HEPES, pH 7.2, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% BSA (bovine serumalbumin). After 30-60 minutes at room temperature, the binding reactionswere filtered through GF/C filters (Whatman glass fiber filters, Type C)or GF/B unifilter plates (Packard) which had been pre-soaked with 0.3%polyethyleneimine and washed twice with binding buffer containing 0.5 MNaCl. Filters were dried and counted in a Beta-Plate scintillationcounter using standard scintillation fluid. Final concentration ofcompound in the binding assay ranged from 0.05-100 μM. Compounds weredissolved in DMSO (dimethyl sulfoxide). Final concentrations of DMSO inthe binding were kept constant at 0.5%.

IC50s were calculated using a non-linear 3-parameter logistic curve fit.IC50 means the concentration at which 50% inhibition is achieved.Negative controls contained the same amount of DMSO vehicle as used inwells containing compound. Positive control contained 250-500 nM coldcompetitor MCP-1 in DMSO vehicle. Non-specific binding (the level ofbound ¹²⁵I-labeled MCP-1 in the presence of 250-500 μM unlabeled MCP-1)was subtracted from all data prior to analysis.

The data in the table below show the MCP-receptor binding activity ofrepresentative benzimidazoles of the present invention.

TABLE 1 Biological Activity: MCP-1 Receptor Binding Assay MCP-1*Structure IC₅₀ [μM]

11.1

13.4

10.9

5.9

9.6

8.7

6.3

15.5

3.1

8.6

12.1

20.7

11.5

15.1

5.1

11.3

15.4

11.9

6.4

3.2

6.7

9.9

4.3

6.8 *Data provided as a range of IC₅₀s from several replications

CD3-Blast Chemotaxis Assay

Recombinant human MCP-1 was obtained from Peprotech (Rockey Hill, N.J.).T lymphocyte blast cells (CD3-Blasts) were generated by standardprotocols (Coligan, J. E., A. M. Kruisbeek, D. H. Macgulies, E. M.Shevach, and W. Strober, editors. 1992. Current Protocols in Immunology.John Wiley and Sons, New York 7.1.2, 7.10.1-7.10.10). Briefly, humanperipheral blood mononuclear cells (PBMC) were isolated from heparinizedvenous blood by Percoll density gradient centrifugation (d=1.088) atroom temperature. RBCs were removed by hypotonic lysis or dextransedimentation. Blast cells were generated by incubating 2×10⁶ PBMC in24-well tissue culture plates that were coated with 2.5 μg of ananti-CD3 monoclonal antibody (identified as TR_(66,) a gift from Dr. A.Lanzivecchia; similar monoclonal antibody is HIT3a, from Parmingen#30111A) at 37° C. for 48 to 72 hours, and then transferring 12 wells toT25 or T75 flasks with RPMI (Roswell Park Memorial Institute 1640, agrowth cell medium available from Gibco/RBL, Inc., N.Y.)+10% FCS (fetalcalf serum)+50 units/ml IL-2. The cells are expanded and cultured for upto 3 weeks. CD3-Blast chemotaxis was assessed no sooner than 3 to 4 daysafter transfer to the IL-2 containing medium using a modification of atransendothelial migration assay (Carr. M. W., S. J. Roth, B. Luther, S.S. Rose, and T. A. Springer. 1994. Monocyte chemoattractant protein 1acts as a T-lymphocyte chemoattractant. Proc. Natl. Acad. Sci. USA91:3652-6). The endothelial cells used for this assay were theendothelial cell line ECV304. (ECV304 was from the European Collectionof Animal Cell Cultures, Porton Downs, U K, assession #92091712).Endothelial cells were cultured on 6.5 mm diameter Transwell cultureinserts (Costar) with a 3.0 mm pore size. Culture media for ECV304 cellsconsisted of M199 (a cell culture medium from Gibco BRL, Inc.,Gaithersburg, Md.)+10% FCS (fetal calf serum from Gibco BRL, Inc.),L-glutamine, and antibiotics (the penicillin concentration was 50 U/mL,and the streptomycin concentration was 50 μg/mL; both from Gibco, N.Y.).Assay media consisted of equal parts RPMI 1640 and M199, with 0.5% BSA(bovine serum albumin or simply RPMI 1640 with 0.5% BSA). Twenty fourhours before the assay, 2×10⁵ ECV304 cells were plated onto each insertof the 24 well chemotaxis plate and incubated at 37° C. MCP-1 (About 10nM diluted in assay medium) with or without compounds, was added to thewells of a 24-well tissue culture plate in a final volume of 600 mL.Endothelial coated Transwells were inserted into each well and 10⁶CD3-blasts were added to the top chamber in a final volume of 100 mL,with or without compounds. The plate was then incubated at 37° C. in 5%CO₂ 95% air for approximately 1 hour. The cells that had migrated to thebottom chamber were enumerated using flow cytometry. 500 mL of the cellsuspension from the lower chamber was placed in a tube, and relativecell counts were obtained by acquiring events for a set time period of30 seconds. This counting method was found to be highly reproducible,and enabled gating on the leukocytes and the exclusion of debris orother cells. Background migration was determined by counting cells thatmigrated in the absence of MCP-1 in the lower chamber. This backgroundmigration of cells per 30 second count was subtracted from the migrationto MCP-1 to obtain specific migration. The percent inhibition bycompounds of directed migration was determined by the following formula:$1 - \left\lbrack \frac{Mc}{Mo} \right\rbrack$

where Mc=the specific migration in the presence of compound and Mo=thespecific migration in the absence of compound.

TABLE II CD3 Chemotaxis Assay

% Inhibition of Example R Chemotaxis at 10 μM 1 N(C₂H₄NEt₂)₂ 62-142* 2—N(CH₃)-2-[N-Piperdine]Ethyl 100, 102** 3 —N(CH₃)(C₂H₄NEt₂) 95, 102***Data presented as a range from several replications **Data from twoseparate experiments

Streptococcal Cell Wall Arthritis

Streptococcal cell wall (SCW) arthritis is induced in female Lewis rats(200 g). To induce the subacute, transient arthritic response, a highlyrefined preparation of streptococcal cell walls (100P, Lee Laboratories,Grayson, Ga.) is injected into the ankle joints of female Lewis rats (6μl/rat in Dulbecco's PBS). Twenty one days later, the animals are givenan IV booster of SCW at a dose of 100 μg/rat in 0.25 mL of Dulbecco'sPBS. Vehicle (0.5% hydroxypropylmethylcellulose and 0.2% Tween 80, 10mL/kg) or test compounds suspended in vehicle is given one hour beforethe IV challenge with SCW and daily thereafter for 3 additional days.Paw volume is measured daily by mercury plethysmography. Swelling wasdetermined by comparing paw volume at the various timepoints with aninitial paw volume measurement for each rat. Percent inhibition ofswelling in compound-treated rats is determined in comparison withswelling in rats treated with vehicle. Statistical power is calculatedusing an analysis of covariance with a contrast mean comparison test(n=5-10 per experimental group).

Glucan Vasculitis Model

Pulmonary granulomatous vasculitis was induced in anesthetized, 150-20 gmale Lewis rats by intravenous infusion of 5 mg glucan. Infusion ofparticulate yeast cell-wall glucan into rats results in the rapid andsynchronous development of angiocentric pulmonary granulomas which arecomposed almost entirely of monocytes and macrophages. It has been shownpreviously that MCP-1 mRNA expression and MCP-1 activity in lung lavagefluid rise in association with pulmonary granuloma development, and thatgranuloma development is markedly attenuated in rats treated withneutralizing concentrations of anti-MCP-1 antibody. This suggests thatMCP-1 plays a pivotal role in the pathogenesis of glucan-inducedgranulomatous vasculitis. For these studies, compound was given by oralgavage at the indicated doses one hour prior to, and then twenty-fourand forty-eight hours after glucan infusion. The rats were sacrificedseventy-two hours after the glucan infusion. At the time of sacrifice,the lungs were lavaged with 6.0 mLs. PBS/EDTA. Total cell counts in therecovered lavage fluid were obtained on a coulter counter, andcytocentrifuge preparations were prepared for differential cell counts.Following the lavage, the lungs were fixed with 10% neutral bufferedformalin for routine processing and histological assessment of pulmonaryvasculitis. The test results are shown in FIG. 1 for Example 1 compound.

Inhibition of T Cell Recruitment to Rat Skin Inflammatory Sites byCompound 1

Method of Evaluation

Inbred, approximately 200 g, male Lewis rats were used in allexperiments. Cutaneous delayed hypersensitivity (DHR) was induced aspreviously described (1). Briefly, rats were sensitized to KLH (SigmaChemical Co., St. Louis, Mo.) by administering 50 μg KLH in 0.1 mLcomplete Freund's adjuvant (CFA; Sigma Chemical Co.) into each of 4subcutaneous sites. After 14 days, DHR was elicited by the challenge of5 μg KLH in PBS into multiple intradermal sites on the back. Analysiswas performed 24 hours after antigen challenge. For each experiment,there were at least three groups of animals of at least four animals ineach group. One group of nonsensitized, naive animals was used as anegative control and received vehicle alone (consisting of 0.5%hydroxypropylmethylcellulose/0.2% Tween 80 in water) per os at the timeof challenge. As positive controls, one group of sensitized animalsreceived alone per os at the time of KLH challenge. A third groupconsisted of sensitized animals that received compound suspended invehicle per os at the time of KLH challenge.

T cell recruitment at sites of DHR was quantified using methodspreviously described (1-4). Briefly, rat T cells were isolated fromspleen of naive adult Lewis rats by mincing the splenic tissue, removingthe red cells by hypotonic lysis, and passing the cells through a nylonwool column. The cells in the effluent were highly purified (>95%) rat Tcells as assessed by anti-rat CD3 (monoclonal antibody KT3, BiosourceInternational, Camarillo, Calif.) immunoreactivity by flow cytometry.Radiolabeling was performed by suspending 5×10⁷ T cells in 0.5 mL RPMI1640 medium with 7.5 μCi¹¹¹In-oxiquinoline (Amersham Corp., ArlingtonHgts, Ill.) for 20 min at room temperature so that 2×10⁷ T cells yieldedapproximately 0.5-2×10⁶ cpm of γ activity. The cells were then washedtwice, resuspended in RPMI 1640 plus 10% normal rat serum, and 2×10⁷labeled T cells/200 gm body weight rat were injected intravenously atthe time of KLH intradermal challenge. Skin challenge sites (8 mm indiameter) were counted on a γ counter 24 hours after injection ofradiolabeled T cells. Lung, liver, and spleen were also collected andcounted as comparative indices for evaluation of input.

Statistical significance was determined using a paired Student's t-test.Differences between means were considered significant when P<0.05.

Results

When administered once per os at the time of antigen challenge, Compound#1 inhibited the recruitment of ¹¹¹ In-labeled rat T cells to skin DHRsites in a dose-dependent fashion (FIG. 2).

References

1. Issekutz, T. B., J. M. Stoltz, and P. V. D. Meide. 1988. Lymphocyterecruitment in delayed-type hypersensitivity: the role of IFN-gamma. JImmunol. 140:2989-2993.

2. lssekutz, T. B. 1991. Inhibition of in vivo lymphocyte migration toinflammation and homing too lymphoid tissues by the TA-2 monoclonalantibody: a likely role for VLA-4 in vivo. J Immunol. 147:4178-4184.

3. Issekutz, T. B. and A. C. lssekutz. 1991. T lymphocyte migration toarthritic joints and dermal inflammation in the rat: differing migrationpatterns and the involvement of VLA-4. Clin. Immunol. Immunopathol.61:436-447.

4. Issekutz, T. B. 1993. Dual inhibition of VLA-4 and LFA-1 maximallyinhibits cutaneous delayed-type hypersensitivity-induced inflammation.Am. J Pathol. 143:1286-1293.

The compounds of the present invention can be prepared and administeredin a wide variety of routes of administration such as parenteral, oral,topical, rectal, inhalation and the like. Formulations will varyaccording to the route of administration selected. Examples are oral andparenteral dosage forms. Thus, the compounds of the present inventioncan be administered by injection, that is, intravenously,intramuscularly, intra-cutaneously, subcutaneously, intraduodenally, orintra-peritoneally. Also, the compounds of the present invention can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally.The following dosage forms may comprise as the active component, acompound of Formula I or a corresponding pharmaceutically acceptablesalt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier can be a finely divided solid which is in amixture with the finely divided active component.

In tablets, the active component can be mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

The powders and tablets preferably contain from 5% or 10% to about 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent can be dispersed homogeneously therein, as by stirring. Themolten homogenous mixture can be then poured into convenient sizedmolds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in apharmaceutically acceptable carrier, such as, aqueous polyethyleneglycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water or another suitable carrierwith viscous material, such as natural or synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted for example from about 0.1 mg to 200 mg, preferablyabout 0.5 mg to 100 mg according to the particular application and thepotency of the active component. The composition can, if desired, alsocontain other compatible therapeutic agents.

In therapeutic use as agents for the treatment of inflammatory diseases,inflammatory diseases, atherosclerosis, restenosis, and immune disorderssuch as arthritis and transplant rejection, the compounds utilized inthe pharmaceutical methods of this invention can be administered at aninitial dosage of about 0.01 mg to about 200 mg/kg daily. A daily doserange of about 0.01 mg to about 50 mg/kg is preferred. The dosages,however, may be varied depending upon the requirements of the patient,the severity of the condition being treated, and the compound beingemployed. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

The ACAT inhibitors, HMG-CoA reductase inhibitors, lipid regulators, andbile acid sequestrants utilized in the second embodiment of the presentinvention can be used in standard dosage amounts known in the art.

As further exemplification of the invention listed below are preferredembodiments wherein all parts are parts by weight and all temperaturesare degrees Centigrade unless otherwise indicated.

EXAMPLE 1

(Compound 1)

Step A: Preparation of 4[bis-(2-diethylamino-ethyl)-amino]benzaldehyde

4-Fluorobenzaldehyde (9.8 g, 80.0 mmol), 1,1,7,7,-tetraethyldiethylenediamine (20 g, 92.8 mmol) and K₂CO₃ (12.8 g, 92.8 mmol) indimethylacetamide (40 mL) are heated to 120° C. with vigorous stirringfor three days. The reaction mixture is cooled, diluted with water (200mL) and extracted with EtOAc (3×200 mL). The organic layer is dried(magnesium sulfate) and concentrated. The product is chromatographed onsilica gel eluting with 0.5% NH₄OH:5.0% MeOH:94.5% CH₂Cl₂ to give 10.2 gof a brown oil.

Step B: Preparation ofN-[4-(5,6-dichloro-1H-benzimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N,N-diethyl-ethane-1,2-diamine

4-[Bis-[2-diethylamino-ethyl)-amino]-benzaldehyde (10 g, 31.3 mmol) andsodium bisulfite (NaHSO₃) (6.76 g) in methanol (300 mL) are heated toreflux for 4 hours. 4,5-Dichlorophenylenediamine (5.54 g, 31.3 mmol) isadded and the reaction mixture is refluxed for 18 hours. The reactionmixture is cooled, filtered through Celite and concentrated in vacuo.The product is chromatographed on silica gel eluting with 0.4%NH₄OH:4.0% MeOH:95.6% CH₂Cl₂ followed by recrystallization from hot 50%EtOH:50% H₂O to give 8.98 g of peach colored needles; mp 129-132° C.

Compounds 2-9 were prepared in a similar fashion.

EXAMPLE 10

Step A: Preparation of4[methyl-(2-piperidin-1-yl-ethyl-amino]acetophenone

4′-Fluoroacetophenone (1.5 g, 10.86 mmol),N-methyl-1-piperidineethanamine (1.54 g, 10.86 mmol) and K₂CO₃ (1.80 g,13.0 mmol) in dimethylacetamide (5 mL) are heated to 100° C. withvigorous stirring for 3 days. The reaction mixture is cooled, dilutedwith water (50 mL), and extracted with EtOAc (3×50 mL). The organiclayer is dried (magnesium sulfate) and concentrated. The product ischromatographed on silica gel eluting with 0.3% NH₄OH:2.7% MeOH:97%CH₂Cl₂ to give 1.95 g of a brown oil.

Step B: Preparation of[4-(5-Chloro-3H-indol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

4[Methyl-(2-piperidin-1-yl-ethyl-amino]acetophenone (1.8 g, 6.91 mmol)and 4-chlorophenylhydrazine hydrochloride are mixed with polyphosphoricacid (15 mL) and heated to 100° C. for 15 minutes. The reaction mixtureis cooled, diluted with water (300 mL), basified with solid NaOH to pH10 and extracted with CH₂Cl₂. The organic layer is dried (magnesiumsulfate) and concentrated. The product is chromatographed on silica geleluting with 3% MeOH:97% CH₂Cl₂ to give 0.611 g of a black solid.Recrystallization from hot EtOH and water gave 0.400 g of the product asa white solid; mp 192° C.

EXAMPLE 2N-[4-(5,6-dichloro-1H-benzimidazol-2-yl)-phenyl]-N-methyl-N-(2-piperidin-1-yl-ethyl)-aminemp 165-167° C. EXAMPLE 3N-[4-(5,6-dichloro-1H-benzimidazol-2-yl)-phenyl]-N-(2-diethylaminoethyl)-N-methyl,N-diethyl-ethane-1,2-diamine mp 124-128° C. EXAMPLE 4[4-[6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-aminemp 196° C. EXAMPLE 5[4-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-aminemp 167-168° C. EXAMPLE 6Methyl-[4-(6-methyl-1H-benzoimidazol-2-yl)-phenyl]—(2-piperidin-1-yl-ethyl)-aminemp 165° C. EXAMPLE 7[4-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-aminemp 194-196° C. EXAMPLE 8[4-(6,7-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-aminemp 164° C. EXAMPLE 9[4-(6-methoxy-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-aminedihydrochloride mp 273° C. EXAMPLE 10[4-(5-Chloro-3H-indol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-aminemp 192° C.

Some preferred compounds are:

N-[4-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[4-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(1H-Benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(1H-Benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine,mp 190-191° C.

N-[4-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[3-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(1H-Benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(1H-Benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[3-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[2-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(1H-Benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(1H-Benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[2-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(1H-Benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{2-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-benzoimidazol-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{3-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-benzoimidazol-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{4-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-benzoimidazol-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[2-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(1H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[2-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(1H-Imidazo[4,5-c]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[2-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(3H-Imidazo[4,5-c]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[2-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[2-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(3H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[2-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[2-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[3-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(1H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[3-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(1H-Imidazo[4,5-c]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(3H-Imidazo[4,5-c]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[3-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(3H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[3-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[3-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[4-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(1H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[4-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(1H-Imidazo[4,5-c]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(3H-Imidazo[4,5-c]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N,N-Diethyl-N′-[4-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(3H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-(2-Dimethylamino-ethyl)-N-[4-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N-[4-(3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[4-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N,N-Diethyl-N′-(2-piperidin-1-yl-ethyl)-N′-[4-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

Methyl-(2-piperidin-1-yl-ethyl)-[4-(7H-purin-8-yl)-phenyl]-amine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[4-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[4-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[3-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N,N-Diethyl-N′-(2-piperidin-1-yl-ethyl)-N′-[3-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

Methyl-(2-piperidin-1-yl-ethyl)-[3-(7H-purin-8-yl)-phenyl]-amine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[3-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[3-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[2-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N,N-Diethyl-N′-(2-piperidin-1-yl-ethyl)-N′-[2-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

Methyl-(2-piperidin-1-yl-ethyl)-[2-(7H-purin-8-yl)-phenyl]-amine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[2-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[2-(7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[2-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N,N-Diethyl-N′-(2-piperidin-1-yl-ethyl)-N′-[2-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

Methyl-(2-piperidin-1-yl-ethyl)-[2-(9H-purin-8-yl)-phenyl]-amine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[2-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[2-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[3-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N,N-Diethyl-N′-(2-piperidin-1-yl-ethyl)-N′-[3-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

Methyl-(2-piperidin-1-yl-ethyl)-[3-(9H-purin-8-yl)-phenyl]-amine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[3-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[3-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[4-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N,N-Diethyl-N′-(2-piperidin-1-yl-ethyl)-N′-[4-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

Methyl-(2-piperidin-1-yl-ethyl)-[4-(9H-purin-8-yl)-phenyl]-amine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[4-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Dimethylamino-ethyl)-N′,N′-dimethyl-N-[4-(9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{2-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-b]pyridin-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{2-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-b]pyridin-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{4-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-b]pyridin-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{2-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-c]pyridin-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{3-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-c]pyridin-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{4-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-c]pyridin-1-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(3-methyl-3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{2-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-c]pyridin-3-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(3-methyl-3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{3-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-c]pyridin-3-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(3-methyl-3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(2-{4-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-imidazo[4,5-c]pyridin-3-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-ethane-1,2-diamine

1-(8-{3-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-purin-7-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(7-methyl-7H-purin-8-yl)-phenyl]-ethane-1,2-diamine

1-(8-{4-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-purin-7-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[2-(9-methyl-9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

1-(8-{2-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-purin-9-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[3-(9-methyl-9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

1-(8-{3-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-purin-9-yl)-ethanone

N-(2-Diethylamino-ethyl)-N′,N′-diethyl-N-[4-(9-methyl-9H-purin-8-yl)-phenyl]-ethane-1,2-diamine

1-(8-{4-[Bis-(2-diethylamino-ethyl)-amino]-phenyl}-purin-9-yl)-ethanone

N-[2-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[2-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[2-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[3-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[3-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2,-diamine

[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[2-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[2-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[3-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[3-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine,mp 156° C.

N-[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine

N-[3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine

N-[3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine,mp 129-132° C.

N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N′,N′-diethyl-N-(2-piperidin-1-yl-ethyl)-ethane-1,2-diamine

[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine,mp 160-163° C.

N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine;and

N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine.

While the forms of the invention herein disclosed constitute presentlypreferred embodiments, many others are possible. It is not intendedherein to mention all of the possible equivalent forms or ramificationsof the invention. It is understood that the terms used herein are merelydescriptive rather than limiting and that various changes may be madewithout departing from the spirit or scope of the invention.

What is claimed is:
 1. A compound of Formula I

wherein A is N; W, X, Y, and Z can be independently C—R₂, C—R₃, C—R₄, orC—R₅, R₂, R₃, R₄, and R₅ can be independently H, C₁₋₂₀ akyl, halogen,nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbon atoms, —S(O)_(p)R where p isan integer of from 0 to 2, —(CH₂)_(m)OR, —(CH₂)_(m)COOR,—(CH₂)_(m)NR₈R₉, —(CH₂)_(m)CONR₈R₉, —(CH₂)_(m)COR, —CF₃, -benzyl, orphenyl wherein benzyl or phenyl is optionally substituted with one ortwo substituents each independently selected from alkyl, halogen,hydrogen, hydroxy, or alkoxy; m is an integer of from 0 to 4, R ishydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10 carbonatoms, or benzyl; when X and Y are substituted by alkyl, they can bejoined to form a ring fused at X and Y; R₁ can be H, lower alkyl of from1-4 carbon atoms, or —(CH₂)_(m)-Ph; R′₂ is: H, C₁₋₂₀ alkyl, halogen,nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbon atoms, —S(O)_(p)R wherein pis an integer of from 0 to 2, —(CH₂)_(m)OR₁—CH₂COOR, —(CH₂)_(m)NR₈R₉,—(CH₂)_(m)CONR₈R₉, —(CH₂)_(m)COR, or —CF₃; R₆ is hydrogen or alkyl offrom 1-6 carbon atoms or R₇; R₇ is (CH₂)_(n)NR₁₀R₁₁; n is an integerfrom 2 to 6; R₈ and R₉ can be independently hydrogen, lower alkyl offrom 1-4 carbon atoms, or can be taken together to form a ring of from3-8 atoms having up to one additional heteroatom as O, S, SO₂, or N—R₁₂;R₁₀ and R₁₁ can independently be lower alkyl, —(CH₂)_(m)Ph,unsubstituted or substituted with up to three R₂ substituents, or R₁₀and R₁₁ can be taken together to form a ring of from 3-8 atoms which maycontain oxygen or NR₁₂; R₁₂ is hydrogen, lower alkyl, —(CH₂)_(t)Ph,where Ph is phenyl unsubstituted or substituted with up to three R₂substituents; t is an integer of from 0 to 2; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein R₁ ishydrogen.
 3. The compound of claim 1 wherein R₁ and R₂′ are hydrogen. 4.A method for the treatment of inflammatory disease or condition,atherosclerosis, restenosis, chronic or acute immune disorders, ortransplant rejection in a mammal in need thereof comprisingadministering to such mammal an effective amount of a compound ofFormula I

wherein A is N; W, X, Y, and Z can be independently C—R₂, C—R₃, C—R₄, orC—R₅, R₂, R₃, R₄, and R₅ can be independently H, C₁₋₂₀ alkyl, halogen,nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbon atoms; —S(O)_(p)R where p isan integer from 0 to 2; —(CH₂)_(m)OR, —(CH₂)_(m)COOR, —(CH₂)_(m)NR₈R₉,—(CH₂)_(m)CONR₈R₉, —(CH₂)_(m)COR, or —CF₃; benzyl, or phenyl whereinbenzyl or phenyl is optionally substituted with one or two substituentseach independently selected from alkyl, halogen, hydrogen, hydroxy, oralkoxy; m is an integer of from 0 to 4, R is hydrogen, lower alkyl offrom 1-4 carbon atoms, aryl of from 6-10 carbon atoms, or benzyl; R′₂is: H, C₁₋₂₀ alkyl, halogen, nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbonatoms, —S(O)_(p)R wherein p is an integer of from 0 to 2,—(CH₂)_(m)OR₁—(CH₂)COOR, —(CH₂)_(m)NR₈R₉, —(CH₂)_(m)CONR₈R₉,—(CH₂)_(m)COR, or —CF₃; R₁ can be H, lower alkyl of from 1-4 carbonatoms, or —(CH₂)_(m)-Ph; R₆ is hydrogen or alkyl of from 1-6 carbonatoms or R₇; R₇ is (CH₂)_(n)NR₁₀R₁₁; n is an integer from 2 to 6; R₈ andR₉ can be independently hydrogen, lower alkyl of from 1-4 carbon atoms,or can be taken together to form a ring of from 3-8 atoms having up toone additional heteroatom as O, S, SO₂, or N—R₁₂; R₁₀ and R₁₁ canindependently be lower alkyl, —(CH₂)_(m)Ph, unsubstituted or substitutedwith up to three R₂ substituents, or R₁₀ and R₁₁ can be taken togetherto form a ring of from 3-8 atoms which may contain oxygen or NR₁₂; R₁₂is hydrogen, lower alkyl, —(CH₂)_(t)Ph, where Ph is phenyl unsubstitutedor substituted with up to three R₂ substituents; t is an integer of from0 to 2; or a pharmaceutically acceptable salt thereof.
 5. The method ofclaim 4 wherein in the compound administered R₂, R₃, R₄, and R₅ arehydrogen.
 6. The method of claim 4 wherein in the compound administeredR₁ is hydrogen.
 7. The method of claim 4 comprising administering thecompound is recited below:


8. The method of claim 4 comprising administering the compound isrecited below:


9. The method of claim 4 wherein in the compound administered R₂, R₃, R₄or R₅, can be independently OH, alkoxy, halogen, —NH₂, -dialkylamino,—NO₂, —CF₃, —SH, or —S-alkyl.
 10. The method of claim 4 wherein in thecompound administered R₁ is alkyl.
 11. The method of claim 4 wherein thedisease or condition may be any one of the following: arthritis,rheumatoid arthritis, osteoarthritis inflammatory bowel diseases,Crohn's disease, ulcerative colitis, multiple sclerosis, idiopathicpulmonary fibrosis, graft rejection, allograft rejection, allergichypersensitivity disorders, asthma and allergic rhinitis, psoriasis,chronic contact dermatitis, sarcoidosis, dermatomyositis, skinphemphigoid, pemphigus vulgaris, p. foliacious, p. erythematosus,glomerulonephritides, vasculitides including necrotizing, cutaneous andhypersensitivity vasculitis; hepatitis, diabetes, systemic lupuserythematosus, myasthenia gravis, dermatitis, eczema, atopic dermatitis,allergic contact dermatitis, urticaria, and reparfusion injury.
 12. Apharmaceutical composition for the treatment of inflammation,atherosclerosis, restenosis, immune disorders, and transplant rejectionin a mammal in need thereof comprising administering to such mammal atherapeutically effective amount of a compound according to claim 1 inadmixture with a pharmaceutically acceptable excipient, diluent, orcarrier.
 13. A method for the treatment of atherosclerosis in a mammalin need thereof comprising administering to such mammal an effectiveamount of a compound of Formula I

wherein A is N; W, X, Y, and Z can be independently C—R₂, C—R₃, C—R₄,C—R₅, R₂, R₃, R₄, and R₅ can be independently: H, C₁₋₂₀ alkyl, halogen,nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbon atoms; —S(O)_(p)R where p isan integer from 0 to 2; —(CH₂)_(m)OR, —(CH₂)_(m)COOR, —(CH₂)_(m)NR₈R₉,—(CH₂)_(m)CONR₈R₉, —(CH₂)_(m)COR, or —CF₃; m is an integer of from 0 to4, R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from6-10 carbon atoms, or benzyl; R₁ can be H, lower alkyl of from 1-4carbon atoms, or —(CH₂)_(m)-Ph; R₆ is hydrogen or alkyl of from 1-6carbon atoms or R₇; R₇ is (CH₂)_(n)NR₁₀R₁₁; n is an integer from 2 to 6;R₈ and R₉ can be independently hydrogen, lower alkyl of from 1-4 carbonatoms, or can be taken together to form a ring of from 3-8 atoms havingup to one additional heteroatom as O, S, SO₂, or N—R₁₂; R₁₀ and R₁₁ canindependently be lower alkyl, —(CH₂)_(m)Ph, unsubstituted or substitutedwith up to three R₂ substituents, or R₁₀ and R₁₁ can be taken togetherto form a ring of from 3-8 atoms which may contain oxygen or NR₁₂; R₁₂is hydrogen, lower alkyl, —(CH₂)_(t)Ph, where Ph is phenyl unsubstitutedor substituted with up to three R₂ substituents; t is an integer of from0 to 2; or a pharmaceutically acceptable salt thereof.
 14. Thecomposition of claim 12 comprising the compound recited below:

wherein X is R₂ and R is —NR₆R₇.
 15. A pharmaceutical composition forthe treatment of atherosclerosis in a mammal in need thereof comprisingadministering to such mammal a therapeutically effective amount of oneor more compounds according to claim 1 in admixture with apharmaceutically acceptable excipient, diluent, or carrier.
 16. A methodof inhibiting the binding of Monocyte Chemoattractant Protein-1 to areceptor thereof in a mammal in need thereof comprising administering tosuch mammal an effective inhibiting amount of a compound of Formula I

wherein A is N; W, X, Y, and Z can be independently C—R₂, C—R₃, C—R₄,C—R₅, R₂, R₃, R₄, and R₅ can be independently H, C₁₋₂₀ akyl, halogen,nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbon atoms, —S(O)_(p)R where p isan integer of from 0 to 2, —(CH₂)_(m)OR, —(CH₂)_(m)COOR,—(CH₂)_(m)NR₈R₉, —(CH₂)_(m)CONR₈R₉, —(CH₂)_(m)COR, —CF₃, -benzyl, orphenyl wherein benzyl or phenyl is optionally substituted with one ortwo substituents each independently selected from alkyl, halogen,hydrogen, hydroxy, or alkoxy; m is an integer of from 0 to 4, R ishydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10 carbonatoms, or benzyl; when X and Y are substituted by alkyl, they can bejoined to form a ring fused at X and Y; R₁ can be H, lower alkyl of from1-4 carbon atoms, or —(CH₂)_(m)-Ph; R′₂ is: H, C₁₋₂₀ alkyl, halogen,nitro, —SO₂NR₈R₉, alkoxy of from 1-4 carbon atoms, —S(O)_(p)R wherein pis an integer of from 0 to 2, —(CH₂)_(m)OR₁—CH₂COOR, —(CH₂)_(m)NR₈R₉,—(CH₂)_(m)CONR₈R₉, —(CH₂)_(m)COR, or —CF₃; R₆ is hydrogen or alkyl offrom 1-6 carbon atoms or R₇; R₇ is (CH₂)_(n)NR₁₀R₁₁; n is an integerfrom 2 to 6; R₈ and R₉ can be independently hydrogen, lower alkyl offrom 1-4 carbon atoms, or can be taken together to form a ring of from3-8 atoms having up to one additional heteroatom as O, S, SO₂, or N—R₁₂;R₁₀ and R₁₁ can independently be lower alkyl, —(CH₂)_(m)Ph,unsubstituted or substituted with up to three R₂ substituents, or R₁₀and R₁₁ can be taken together to form a ring of from 3-8 atoms which maycontain oxygen or NR₁₂; R₁₂ is hydrogen, lower alkyl, —(CH₂)_(t)Ph,where Ph is phenyl unsubstituted or substituted with up to three R₂substituents; t is an integer of from 0 to 2; or a pharmaceuticallyacceptable salt thereof.
 17. A compound according to claim 1 andselected from:Methyl-[4-(1H-naphtho[2,3-d]imidazol-2-yl)-phenyl]-(2-piperidin-1-yl-ethyl)-amine;[4-(1,9-Dihydro-fluoreno[2,3-d]imidazol-2-yl)-phenyl]-(methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(1H-Benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(6-Chloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;Methyl-[4-(6-methyl-1H-benzoimidazol-2-yl)-phenyl]-(2-piperidin-1-yl-ethyl)-amine;[4-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(6-Benzyl-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;Methyl-(2-piperidin-1-yl-ethyl)-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-amine;[4-(6-tert-Butyl-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(6-Butyl-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;Methyl-[4-(6-phenyl-1H-benzoimidazol-2-yl)-phenyl]-(2-piperidin-1-yl-ethyl)-amine;(2-{4-[Methyl-(2-piperidin-1-yl-ethyl)-amino]-phenyl}-3H-benzoimidazol-5-yl)-phenyl-methanone;{4-[6-(3,4-Dichloro-phenoxy)-1H-benzoimidazol-2-yl]-phenyl}-methyl-(2-piperidin-1-yl-ethyl)-amine;{4-[5-(3,4-Dichloro-phenylsulfanyl]-1H-benzoimidazol-2-yl]-phenyl}-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(6-Benzyloxy-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(5,6-Dichloro-1H-benzimidazol-2-yl)-benzyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N′,N′-diethyl-ethane-1,2-diamine;N-[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-N-(2-diethylamino-ethyl)-N-methyl,N-diethyl-ethane-1,2-diamine;[4-(5,6-Dichloro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(6-Fluoro-1H-benzoimidazol-2-yl)-phenyl]-methyl-(2-piperidin-1-yl-ethyl)-amine;[4-(6-Phenyl-1H-benzoimidazol-2-yl)-phenyl]-(2-piperidin-1-yl-ethyl)-amine;and(2-{4-[Methyl-(2-piperidin-1-yl-ethyl)-amino]-phenyl}-3H-benzoimidazol-5-yl)-(5-phenyl-pentyl)-amine.18. The compound of claim 1 wherein R₆ is an alkyl group of from 1 to 6carbon atoms.
 19. The compound of claim 1 wherein R₁₀ and R₁₁ when takentogether form a ring from 3-8 atoms.
 20. The compound of claim 1 whereinR₁₀ and R₁₁ are lower alkyl.
 21. The method of claim 4 wherein in thecompound administered R₆ is an alkyl group of from 1 to 6 carbon atoms.22. The method of claim 4 wherein in the compound administered R₁₀ andR₁₁ when taken together form a ring of from 3-8 atoms.
 23. The method ofclaim 4 wherein in the compound administered R₁₀ and R₁₁ are loweralkyl.
 24. The method of claim 10 wherein in the compound administeredR₆ is an alkyl group of from 1 to 6 carbon atoms.
 25. The method ofclaim 10 wherein in the compound administered R₁₀ and R₁₁ when takentogether form a ring of from 3-8 atoms.
 26. The method of claim 10wherein in the compound administered R₁₀ and R₁₁ are lower alkyl. 27.The method of claim 17 wherein in the compound administered R₆ is analkyl group of from 1 to 6 carbon atoms.
 28. The method of claim 17wherein in the compound administered R₁₀ and R₁₁ when taken togetherform a ring of from 3-8 atoms.
 29. The method of claim 17 wherein in thecompound administered R₁₀ and R₁₁ are lower alkyl.